Immunodeficient mouse strains have played an important role in the analysis of the immune system and the development of animal models for human disease. A broad spectrum of naturally occurring murine immunodeficiencies have been discovered, however, no defects which fully and selectively limit the synthesis of immunoglobulins have been identified. The goal of Phase I study is to generate such an immune deficiency by means of targeted inactivation of murine immunoglobulin heavy and light chain genes in embryonic stem (ES) cells, followed by derivation of mice carrying the inactivated loci. The utility of the resulting mutations resides in their use as a null background for the expression of immunoglobulin transgenes and in their potential for combination with other immuno-deficiencies to generate superior immunodeficient mice. Specifically, in Phase II study, the activated immunoglobulin heavy and light chain loci will be bred into mice expressing human immunoglobulin transgenes, under development at GenPharm, to generate a mouse from which human MAbs can readily be isolated. In addition, the heavy chain mutation will also be introduced into SCID mice, or transgenic immunodeficient (TIM) mice under development at GenPharm, to eliminate "leaky" or residual antibody synthesis and provide a more efficient host for engraftment of human tissues.